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Updated: Jul 4, 2025
Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Signaling from RAS to RAF: The Molecules and Their Mechanisms
Hyesung Jeon1,2, Emre Tkacik1,3, Michael J Eck1,2
1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA;
Abstract:
RAF family protein kinases are a key node in the RAS/RAF/MAP kinase pathway, the signaling cascade that controls cellular proliferation, differentiation, and survival in response to engagement of growth factor receptors on the cell surface. Over the past few years, structural and biochemical studies have provided new understanding of RAF autoregulation, RAF activation by RAS and the SHOC2 phosphatase complex, and RAF engagement with HSP90-CDC37 chaperone complexes. These studies have important implications for pharmacologic targeting of the pathway. They reveal RAF in distinct regulatory states and show that the functional RAF switch is an integrated complex of RAF with its substrate (MEK) and a 14-3-3 dimer. Here we review these advances, placing them in the context of decades of investigation of RAF regulation. We explore the insights they provide into aberrant activation of the pathway in cancer and RASopathies (developmental syndromes caused by germline mutations in components of the pathway).
Insights
Recent studies reveal RAF protein kinase regulation, crucial for cell growth. Understanding these distinct states and complexes offers new therapeutic targets for cancer and developmental disorders.
Area of Science:
- Molecular Biology
- Cell Signaling
- Biochemistry
Background:
- RAF kinases are central to the RAS/RAF/MAP kinase pathway, regulating cell proliferation, differentiation, and survival.
- Growth factor receptor activation initiates this critical signaling cascade.
- Aberrant pathway activation is implicated in various cancers and RASopathies.
Purpose of the Study:
- To review recent structural and biochemical advances in understanding RAF protein kinase regulation.
- To explore the implications of these findings for pharmacologic targeting of the RAS/RAF/MAP kinase pathway.
- To contextualize new insights within the broader history of RAF regulation research.
Main Methods:
- Review of recent structural and biochemical studies on RAF autoregulation and activation.
- Analysis of RAF interactions with RAS, SHOC2 phosphatase, and HSP90-CDC37 chaperone complexes.
- Examination of the integrated RAF-MEK-14-3-3 complex as the functional RAF switch.
Main Results:
- New understanding of RAF autoregulation, activation mechanisms, and chaperone interactions.
- Identification of distinct regulatory states of RAF protein kinases.
- Characterization of the functional RAF switch as a complex involving RAF, MEK, and 14-3-3 dimers.
Conclusions:
- Recent advances provide critical insights into RAF kinase regulation and its role in disease.
- Understanding RAF's distinct regulatory states and activation complexes is key for targeted therapies.
- These findings have significant implications for treating cancers and RASopathies driven by pathway dysregulation.
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